Gender differences in prevalence, diagnosis and ...

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Feb 14, 2012 - Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. .... Correspondence to Dr Alan G Dawson, Academic Foundation Year ...

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Gender differences in prevalence, diagnosis and incidence of allergic and non-allergic asthma: a population-based cohort Be´ne´dicte Leynaert,1,2,3 Jordi Sunyer,4,5,6,7 Raquel Garcia-Esteban,4,5,7 Cecilie Svanes,8,9 Deborah Jarvis,10 Isa Cerveri,11 Julia Dratva,12,13 Thorarinn Gislason,14 Joachim Heinrich,15 Christer Janson,16 Nino Kuenzli,12,13 Roberto de Marco,17 Ernst Omenaas,8,18 Chantal Raherison,19 Francisco Go´mez Real,8,20 Matthias Wjst,21,22 Elisabeth Zemp,12,13 Mahmoud Zureik,1,2 Peter G J Burney,10 Josep M Anto,4,5,6,7 Franc¸oise Neukirch1,2 < Additional materials are

published online only. To view these files please visit the journal online (http://thorax.bmj. com/content/67/7.toc). For numbered affiliations see end of article. Correspondence to Be´ne´dicte Leynaert, INSERM Unite´ 700, Epide´miologie e Faculte´ de Me´decine X, Bichat, 16 Rue Henri Huchard, Paris 75018, France; [email protected] Received 17 October 2011 Accepted 12 January 2012 Published Online First 14 February 2012

ABSTRACT Background Although women with severe non-allergic asthma may represent a substantial proportion of adults with asthma in clinical practice, gender differences in the incidence of allergic and non-allergic asthma have been little investigated in the general population. Methods Gender differences in asthma prevalence, reported diagnosis and incidence were investigated in 9091 men and women randomly selected from the general population and followed up after 8e10 years as part of the European Community Respiratory Health Survey. The protocol included assessment of bronchial responsiveness, IgE specific to four common allergens and skin tests to nine allergens. Results Asthma was 20% more frequent in women than in men over the age of 35 years. Possible underdiagnosis of asthma appeared to be particularly frequent among non-atopic individuals, but was as frequent in women as in men. The follow-up of subjects without asthma at baseline showed a higher incidence of asthma in women than in men (HR 1.94; 95% CI 1.40 to 2.68), which was not explained by differences in smoking, obesity or lung function. More than 60% of women and 30% of men with new-onset asthma were non-atopic. The incidence of non-allergic asthma was higher in women than in men throughout all the reproductive years (HR 3.51; 95% CI 2.21 to 5.58), whereas no gender difference was observed for the incidence of allergic asthma. Conclusions This study shows that female sex is an independent risk factor for non-allergic asthma, and stresses the need for more careful assessment of possible non-allergic asthma in clinical practice, in men and women.

INTRODUCTION The prevalence of asthma shows a sex reversal around puberty from a higher risk in boys early in life to a higher risk in girls after adolescence.1e6 This pattern has raised several hypotheses about the susceptibility to asthma of men and women, such as an effect of sex hormones, airway calibre, obesity, differences in exposure or diagnosis.1e6 Further studies are needed to appraise how much Thorax 2012;67:625e631. doi:10.1136/thoraxjnl-2011-201249

Key messages What is the key question? < Are women really at increased risk of asthma,

and what could explain this difference?

What is the bottom line? < Women were found to be at increased risk of

developing non-allergic asthma (no difference was found for allergic asthma), and this increased risk was not explained by differences in diagnosis, lung function (as a surrogate of airway calibre), obesity or smoking.

Why read on? < Our data provide evidence that non-allergic

asthma is still poorly recognised in men and women, and that women are at increased risk of developing non-allergic asthma compared with men. We suggest that sex hormones or other biological markers that significantly differ between men and women (such as adipocytes) may be involved in the development of nonallergic asthma.

these determinants could explain the higher risk of asthma in women. Data are lacking on whether women remain at increased risk of asthma throughout all the reproductive years, and few studies have investigated the possibility of a differential diagnosis.2e8 Furthermore, most studies are not of a prospective nature that allows separating new-onset asthma from persistent asthma or relapse. In addition, new-onset of non-allergic asthma appears to be relatively frequent in adulthood.9 Clinical studies suggest that non-allergic (or ‘intrinsic’) asthma may be more severe and difficult to control than allergic asthma, and that women might be at increased risk of non-allergic asthma.10e14 However, most of our knowledge on non-allergic asthma comes from clinical studies which often include patients with more severe asthma, and little is known on non-allergic asthma in the general population.14 625

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Epidemiology We used data collected as part of the European Community Respiratory Health Survey (ECRHS) to estimate gender differences in the prevalence of asthma according to age; appraise possible differences in asthma diagnosis; prospectively investigate gender differences in the remission/persistence of asthma; and assess gender differences in the risk of new-onset asthma, accounting for potential confounders and considering allergic and non-allergic asthma separately, within the age range 20e55 years.

METHODS Study design The analysis is based on data collected in 29 centres from 14 countries as part of the ECRHS. The protocol and participation rates have been described elsewhere.15e17 Briefly, between 1991 and 1993, each participating centre randomly selected about 1500 men and 1500 women, representative of the age group 20e44 years, to answer a postal questionnaire (European Community Respiratory Health Survey I [ECHRS-I] stage 1; ‘screening’). A 20% random sample of respondents was then invited to a clinical investigation (ECHRS-I stage 2). Participants in stage 2 were eligible for the follow-up survey in 1998e2002 (ECRHS-II). At ECHRS-I stage 2 (‘baseline’) and follow-up, the protocol included assessment of respiratory symptoms via questionnaire and measurements of bronchial responsiveness and IgE specific to four common allergens. In each centre, the protocol was approved from the appropriate ethics committee, and written consent was obtained from each participant.

Analysis Doctor-diagnosed asthma was defined as a positive answer to the questions ‘Have you ever had asthma?’ and ‘Was this confirmed by a doctor?’ Because only specific IgEs were assessed at follow-up, the main analysis was conducted with atopy defined as specific IgE$0.35 kU/litre to any of the four common allergens tested. In a sensitivity analysis, atopic status was defined according to specific IgE and skin test reactivity measured at the baseline survey for nine common allergens. Atopic subjects with asthma were considered to have ‘allergic asthma’. Further details including cross tables are provided in the online supplement. All the analyses were conducted in Stata V.8 (StataCorp 2001).

RESULTS Gender differences in asthma prevalence and diagnosis Participation of men and women at each step of the survey is described in the online supplement.

Prevalence At ECRHS-I stage 1 (table 1, first column), large representative samples were screened to estimate asthma prevalence.15 There was no gender difference in the prevalence of asthma from age 20 to 35 years. However, women had a 20% higher risk of asthma than men after age 35 years. This pattern of results was consistent across the participating centres, despite large geographical variations in the prevalence of asthma. To assess whether the magnitude of the gender difference had changed over time, we considered prevalence at ECRHS-II. Although the prevalence of asthma was higher at ECRHS-II, within each age-group the ORs for the gender difference were remarkably similar at each survey, showing no difference before age 35 and a 20% higher risk of asthma in women in the age 626

group 36e44 years (table 1, third column). The higher risk of asthma in women appears to be further marked after age 45 years (OR 1.68; 95% CI 1.24 to 2.29).

Investigating possible differential diagnosis We considered data collected at ECRHS-I stage 2 (including bronchial hyperresponsiveness [BHR] assessment) to assess whether the higher prevalence of asthma in women could be explained by differences in diagnosis. Besides diagnosed asthma, women were also more likely than men to have asthma-like symptoms or asthma-like symptoms and BHR (table 1 and online supplement). Furthermore, among subjects with respiratory symptoms and BHR (table 2), the likelihood of having received a diagnosis of asthma decreased with increasing smoking and was higher in atopic than in non-atopic subjects. However, in each group, it was similar or even lower in women than in men. As shown in table 2, in non-atopic subjects, only 16% of those with asthma-like symptoms and BHR reported a diagnosis of asthma. However, this low rate of diagnosis was similar in women and in men. No major gender difference was observed for asthma treatment, apart from a more frequent use of inhaled steroids in women (online supplement, table E2).

Gender differences in the natural history of asthma Forty-three per cent of men and 63% of women with a current diagnosis of asthma from the doctor at follow-up reported asthma onset in adulthood (online supplement, table E2).

Asthma remission, persistence and relapse in subjects with asthma at baseline Women with current asthma at baseline were as likely as men to still have asthma at follow-up (asthma persistence: 68.1% in 213 women vs 74.1% in 135 men; p>0.20). In subjects who had ever had asthma before the baseline survey, but without ‘current’ asthma at baseline, women were as likely as men to have current asthma at follow-up (asthma relapse after remission: 21.2% in 189 women vs 18.0% in 178 men; p>0.30).

Asthma incidence The risk of developing asthma over the follow-up was investigated in the 4281 women and 3956 men without asthma at baseline (figure 1). The asthma incidence rate was higher in women than in men (table 3). There was no interaction with age (p for interaction ¼0.13). At baseline, women more frequently reported rhinitis, respiratory infections in childhood and maternal asthma compared with men. Women less frequently had positive specific IgE to dust mites and grass, had lower total IgE and smoked less than men. Women had lower body mass index (BMI) than men at baseline and at follow-up, but the mean increase in BMI between the two surveys was slightly higher in women than in men. Adjustment for the subject’s characteristics at baseline or follow-up had little effect on the gender difference in incidence (online supplement, table E3). The risk of developing asthma remained significantly higher in women than in men after adjustment for centre, maternal asthma, smoking, total IgE, atopic sensitisation, rhinitis, forced expiratory volume in 1 s (FEV1) and BMI at baseline (HR 1.94; 95% CI 1.40 to 2.68) as well as after additional adjustment for change in smoking status and change in BMI (HR 2.25; 95% CI 1.57 to 3.23). Further adjustment for occupational exposure over the follow-up to agents known to be related to occupational Thorax 2012;67:625e631. doi:10.1136/thoraxjnl-2011-201249

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Epidemiology Table 1 Prevalence of asthma in representative samples of men and women screened for asthma at ECRHS-I, and in men and women participating in ECHRS-I, stage 2 (1991e1993) and ECHRS-II (1998e2002) ECRHS-I screening (N[87 188)

ECRHS-I, stage 2 (N[15 483)

Current asthma (number of cases/number of subjects included*) % Age 20e27 years Men (731/12 897) 5.67 (103/1998) 5.16 Women (769/13 694) 5.62 (114/2099) 5.43 ORy 0.98 (95% CI 0.88 to 1.09) 1.06 (95% CI 0.80 to 1.39) Age 28e35 years Men (622/13743) 4.53 (97/2371) 4.09 Women (696/14655) 4.75 (110/2670) 4.12 OR 1.03 (95% CI 0.92 to 1.16) 1.01 (95% CI 0.76 to 1.33) Age 36e44 years Men (641/14608) 4.39 (95/2803) 3.39 Women (841/15909) 5.29 (141/3004) 4.69 OR 1.21 (95% CI 1.09 to 1.34) 1.40 (95% CI 1.08 to 1.83) Age 45e52 years Men Women OR Doctor-diagnosed current asthma (n/N) % Men (269/7411) 3.63 Women (351/8053) 4.36 OR 1.21 (95% CI 1.03 to 1.42) Subjects reporting $3 asthma-like symptomsz (n/N) % Men (467/7418) 6.30 Women (628/8065) 7.79 OR 1.26 (95% CI 1.11 to 1.42) Asthma-like symptoms plus bronchial hyperresponsiveness (n/Nx) % Men (308/6809) 4.52 Women (464/7092) 6.54 OR 1.48 (95% CI 1.27 to 1.71)

ECRHS-II (N[9091)

e e e (62/940) 6.60 (64/1016) 6.30 0.95 (95% CI 0.66 to 1.37) (89/1551) 5.74 (120/1751) 6.85 1.21 (95% CI 0.91 to 1.60) (70/1491) 4.69 (124/1648) 7.52 1.68 (95% CI 1.24 to 2.29) (220/4317) 5.10 (304/4753) 6.40 1.27 (95% CI 1.06 to 1.52) (227/4326) 5.25 (338/4765) 7.09 1.38 (95% CI 1.16 to 1.64) (147/3853) 3.82 (230/4072) 5.65 1.51 (95% CI 1.22 to 1.87)

*1190 subjects with age at screening >44 years and 492 subjects with data on ‘current asthma’ missing at the screening survey were not included. For ECRHS-I stage 2 the corresponding figures are 519 and 19. For ECRHS-II, 673 subjects with age >52 years and 21 with data on ‘current asthma’ missing were not included. yOR >1 indicates a higher prevalence in women compared with men. For ECRHS-I screening the ORs are Mantel-Haenszel OR stratified for centre. Within each age group, Breslow-Day tests for heterogeneity across centres were all not significant (p>0.30). Other ORs are crude estimates. zNumber of positive answers to any of the five following items: breathless while wheezing, woken up with a feeling of chest tightness, attack of shortness of breath at rest, attack of shortness of breath after exercise, and woken by an attack of shortness of breath. xSubjects were only included if they did not have missing values for the BHR test. ECHRS, European Community Respiratory Health Survey.

asthma did not change the estimate (HR 2.25; 95% CI 1.54 to 3.29).

Incidence of allergic and non-allergic asthma Women were at greater risk of developing non-allergic asthma than allergic asthma: 65% of the women with new-onset asthma had no atopic sensitisation at follow-up. In men, 37% of incident asthma cases were non-atopic. No gender difference was observed for the incidence of allergic asthma (p>0.60; table 3). In contrast, the incidence of non-allergic asthma was significantly higher in women than in men (HR 3.51; 95% CI 2.21 to 5.58; p

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